DEMOGRAPHIC AND CLINICAL CHARACTERISTICS
Demographic and clinical data on the 244 subjects are presented in . Overall, the subjects were a well-educated group made up of more women than men. Of the group with a CDR of 0.5 (n=167), 42 subjects met MCI criteria and the remaining 125 were designated as having vMCI. The normal group (n=77) had a mean CDR-SB score slightly higher than 0 because 2 individuals had scores of 0.5 in 1 nonmemory CDR category but still carried an overall CDR of 0.32
No differences were detectable among the groups in age, education, or sex.
Demographic, Clinical, and Neuropsychological Characteristics of Sample
LIKELIHOOD OF PROBABLE AD AND DECLINE IS ELEVATED IN THE vMCI SUBGROUP
The subjects in this study were followed up longitudinally for a mean (SD) of 4.5 (0.2) years (range, 3.8-6.9 years). Over this period, 107 of the 244 participants (44%) demonstrated clinical decline (increase in CDR-SB≥1.0), of whom 42 (17% of the sample) were diagnosed with probable AD. Seven individuals were diagnosed with non-AD dementias and were excluded from further analyses.
We first performed analyses to determine whether individuals designated as having vMCI (n=125) were more likely to be diagnosed with probable AD dementia or to decline than normal individuals. Compared with normal individuals, members of the vMCI group were more likely to be diagnosed with probable AD (20% vs 0%;
<.001) or to decline (49% vs 28%;
<.002). The subjects with MCI were more likely than normal individuals to be diagnosed with AD (41%;
<.001) or to decline (62%;
<.001) and were more likely than subjects with vMCI to be diagnosed with AD (
<.01). The illustrates these data.
Figure Proportion of baseline clinical groups that met outcomes of probable Alzheimer disease (AD) diagnosis and clinical decline (increase in Clinical Dementia Rating sum of boxes ≥1.0) within 5 years of follow-up. Subjects with very mild cognitive (more ...)
With regard to the decline end point, some individuals in each group who did not meet the end point declined by 0.5 unit on the CDR-SB (normal, 19%; vMCI, 15%; MCI, 13%), some did not change (normal, 52%; vMCI, 24%; MCI, 13%), and others improved by 0.5 or 1 unit (vMCI, 12%; MCI, 11%). Of those who met the end point, there was a range of decline over the 5-year period, with some individuals declining by 1 to 1.5 units (normal, 22%; vMCI, 21%; MCI, 10%), others declining by 2 to 3 units (normal, 6%; vMCI, 14%; MCI, 32%), and others declining by greater than 3 units (normal, 1%; vMCI, 14%; MCI, 21%).
PREDICTION OF PROBABLE AD AND DECLINE WITHIN THE ENTIRE SAMPLE
We next sought to determine whether graded measures of impairment (based on CDR-SB or neuropsychological test scores) would be useful in the assessment of the likelihood of a diagnosis of probable AD or decline in the entire sample. shows the results of logistic regression models predicting these outcomes. Baseline CDR-SB was strongly associated with the likelihood of probable AD; a logistic regression model predicting AD as a function of degree of baseline CDR-SB, adjusted for age, sex, and education, indicated a nearly 5-fold increase in the likelihood of AD dementia per point in baseline CDR-SB (odds ratio [OR], 4.8; 95% confidence interval [CI], 3.0-7.8; P=.001). Adjusted univariate logistic regression models also showed that the likelihood of probable AD was predicted by all neuropsychological test results examined (ORs, 0.57-0.62). Similar results, generally showing more modest effects, were observed for the decline outcome (OR, 2.25 per point of CDR-SB; OR, 0.64-0.78 for neuropsychological test measures). (For the interpretation of ORs, a higher CDR-SB indicates more prominent symptoms and is scaled in points on the CDR-SB, while higher neuro-psychological test scores indicate better performance and are scaled in standard deviation units. For example, for these univariate analyses, an additional point on the CDR-SB results in nearly a 5-fold increase in likelihood, while 1 SD better performance in verbal memory results in a decrease in likelihood by nearly one-half.)
Adjusted Univariate Analyses of Baseline Clinical and Neuropsychological Measures Predicting Probable AD Diagnosis or Subsequent Cognitive Decline (CDR-SB Increase ≥ 1.0) Over Approximately 5-Year Follow-up Perioda
Multivariate logistic regression models demonstrated that the likelihood of probable AD was predicted by a model including CDR-SB, verbal memory, and executive function (overall model, χ2=78.3; P<.001). Specifically, an AD diagnosis was predicted by CDR-SB (OR, 4.8; 95% CI, 2.8-8.1; P=.001), verbal memory (CVLT delayed retention, OR, 0.67; 95% CI, 0.48-0.94; P=.02), and executive function (Trails B, OR, 0.58; 95% CI, 0.39-0.88; P=.01). For the decline outcome, a multivariate model including clinical impairment (CDR-SB), verbal memory, and executive function (overall model, χ2=53.6; P<.001) was predictive. Specifically, decline was predicted by CDR-SB (OR, 2.06; 95% CI, 1.5-2.9; P<.001), verbal memory (Free and Cued Selective Reminding Test, OR, 0.72; 95% CI, 0.54-0.95; P=.02), and executive function (Self-Ordering Test, OR, 0.75; 95% CI, 0.57-0.99; P<.05). Thus, CDR-SB, verbal memory performance, and executive function performance are useful together in the prediction of a clinical diagnosis of AD and decline.
PREDICTION OF PROBABLE AD AND DECLINE WITHIN THE vMCI SUBGROUP
We then investigated whether the grading of impairment (based on CDR-SB or neuropsychological test scores) within the vMCI subgroup would be useful for predicting AD dementia and decline. As earlier, each of the key predictors was analyzed in separate univariate logistic regression models for each clinical group (). In multivariate analyses within the vMCI group, the likelihood of a diagnosis of probable AD was predicted by both CDR-SB (OR, 2.13; 95% CI, 1.08-4.18; P=.03) and executive function (Trails B, OR, 0.56; 95% CI, 0.35-0.91; P=.02). Likelihood of decline was predicted by CDR-SB (OR, 1.78; 95% CI, 1.02-3.07; P=.04). The CVLT was less powerful in prediction within the vMCI group because the diagnostic criteria used in defining vMCI truncated the distribution of values. Separate analyses are not presented for the MCI group because of its small sample size.
LONGER-TERM OUTCOME OF PARTICIPANTS WITH CLINICAL DECLINE
To examine the clinical significance of the intermediate outcome measure, decline, longer-term follow-up data were used to assess future clinical course in participants who met this outcome. Of the 107 subjects who met the clinical decline outcome within 5 years of initial follow-up, 27 individuals had at least 5 additional follow-up visits after the first visit, at which the decline end point had been met. Of these 27 subjects who declined, 17 (63%) ultimately were diagnosed with dementia after longer follow-up (mean time to dementia diagnosis after initial decline, 6.1 years; 14 with AD and 3 with non-AD dementias). Of the remaining 10 individuals, 6 declined by at least another 1.0 in CDR-SB but did not have dementia at last evaluation (mean follow-up time after initial decline, 9.5 years). The other 4 remained stable after having experienced the initial decline; none of these individuals improved after the initial decline (mean follow-up time after initial decline, 8.8 years). Additional details on longer-term outcome of those who declined are presented in .
Longer-term Outcome of Individuals Demonstrating Cognitive Decline Within First 5 Years of Follow-up by Baseline Status
Of the 244 subjects in the present analyses, 13 individuals died and underwent autopsy. Eight had a diagnosis of probable AD at the last clinical visit prior to death, 5 of whom had pathological changes consistent with a high probability of AD at autopsy33
; 1 also had Lewy body pathological features. Of the remaining 3, 1 had diffuse Lewy bodies and a lesser degree of AD pathological features, 1 had both AD and cerebrovascular pathological features, and the third had mild AD changes but did not meet pathological criteria. Two of the 13 autopsied subjects had a diagnosis of vascular dementia at their last clinical visit and both demonstrated only cerebrovascular disease at autopsy. Three of the 13 autopsied subjects died with a most recent CDR of 0.5, 2 of whom showed evidence of only cerebrovascular pathological features; the other had no obvious pathological features.